Cellular responses to growth factors and cytokines are characterized by the activation of signal transduction pathways, including the Signal Transducer and Activator of Transcription (STAT) family of cytoplasmic transcription factors (Darnell et al., 1994; Schindler et al., 1995; Darnell, 1997; Stark et al., 1998). Activation of STAT proteins is initiated upon their tyrosine phosphorylation, a key event in the formation of phosphotyrosine-SH2 (pTyr-SH2) interactions and the dimerization between two STAT monomers. In turn, dimers of STATs translocate to the nucleus and bind to specific DNA-response elements, thereby inducing the expression of genes essential for cellular responses. Normal physiological functions of STATs include regulation of cell proliferation, differentiation, development and apoptosis (reviewed in (Bromberg et al., 1996; Fukada et al., 1996; Kotenko et al., 2000; Smithgall et al., 2000; Hirano et al., 2000; Akira, 2000)).
In contrast to the tightly-regulated normal STAT signaling, constitutive activation of STAT proteins is frequently observed in human tumors (Turkson et al., 1998; Bromberg et al., 1998) and has been linked to tumor progression. Persistent activation of one STAT family member, Stat3, is detected in breast cancer, prostate cancer, head and neck squamous cell carcinoma, as well as in lymphomas and leukemias (Garcia et al., 1997; Nielsen et al., 1997; Catlett-Falcone et al., 1999; Nielsen et al., 1999; Bromberg, 2000; Grandis et al., 2000; Garcia et al., 2001; Epling-Burnette et al., 2001), reviewed in (Bowman et al., 2000a; Turkson et al., 2000; Song et al., 2000; Coffer et al., 2000; Lin et al., 2000; Buettner et al., 2002; Yu et al., 2004; Turkson, 2004a). In malignant cell lines and tumors that harbor constitutively-active Stat3, studies also reveal overexpression of Stat3-regulated genes encoding the anti-apoptotic proteins Bcl-xL and Mcl-1, the cell cycle regulators, Cyclin D1 and c-Myc, the angiogenesis factor, VEGF, as well as altered expression of immune-modulatory factors (Catlett-Falcone et al., 1999; Nielsen et al., 1999; Grandis et al., 2000; Epling-Burnette et al., 2001; Bowman et al., 2000b; Niu et al., 2002; Wang et al., 2004a). These abnormal gene expression changes contribute to dysregulated cell cycle progression, survival and angiogenesis, and to repressed host immune functions (reviewed in (Yu et al., 2004; Turkson, 2004b)). Thus, inhibition of abnormal Stat3 signaling is sufficient to repress the induction of these genes, resulting in cell cycle arrest and apoptosis of malignant cells (Catlett-Falcone et al., 1999; Grandis et al., 2000; Epling-Burnette et al., 2001; Niu et al., 1999), sensitization of tumor cells to chemotherapy-induced apoptosis (Oshiro et al., 2001), anti-tumor immune responses (Wang et al., 2004a), and tumor regression (Niu et al., 1999). Small-molecule inhibitors of Stat3, therefore, have the potential to impact tumors that harbor constitutively-active Stat3 with significant clinical benefits.
Previous studies have implicated signal transduction pathways in the antitumor activity of platinum complexes. Evidence shows that Cisplatin might modulate the mitogen-activated protein kinase family and the PI-3-kinase/Akt pathway (Sanchez-Perez et al., 1998; Persons et al., 1999; Bose, 2002; Siddik, 2003). Platinum complexes that inhibit Stat3 signaling and induce tumor regression have previously been reported (Turkson et al., 2004b).